RT Journal Article
SR Electronic
T1 Statin-Induced Inhibition of 3-Hydroxy-3-Methyl Glutaryl Coenzyme A Reductase Sensitizes Human Osteosarcoma Cells to Anticancer Drugs
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 595
OP 600
DO 10.1124/jpet.108.136127
VO 325
IS 2
A1 Fromigué, Olivia
A1 Hamidouche, Zahia
A1 Marie, Pierre J.
YR 2008
UL http://jpet.aspetjournals.org/content/325/2/595.abstract
AB Osteosarcoma is the most common primary bone tumor in children and young adults. Resistance to chemotherapeutic drugs is a major problem that is responsible for the failure of treatment. This points to the need for increasing the responsiveness to cytotoxic drugs. We previously showed that lipophilic statins induce apoptosis in human osteosarcoma cells. In this study, we investigated the effects of atorvastatin [(3R,5R)-7[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoïc acid] in combination with chemotherapeutic drugs on human osteosarcoma cell apoptosis, invasion, and migration. We report here that atorvastatin enhances the reduced cell viability induced by the anticancer drugs doxorubicin (Adriamycin; (1S,3S)-amino-3 tridesoxy-2,3,6 α-l-lyxo-hexopyranoside glycoloyl-3 trihydroxy-3,5,12 methoxy-10 dioxo-6,11 naphtacenyl-1) and cisplatin in human osteosarcoma cells. In particular, we found that atorvastatin enhances the induction of osteosarcoma cell apoptosis by anticancer drugs. In addition, we show that atorvastatin enhances the inhibitory effect of anticancer drugs on osteosarcoma cell migration. Moreover, atorvastatin and chemotherapeutic drugs had additive inhibitory effects on osteosarcoma cell invasion. In consistent tests, atorvastatin further augmented the reduction of matrix metalloprotease 2 activity induced by doxorubicin or cisplatin in osteosarcoma cells. The results show for the first time that atorvastatin sensitizes osteosarcoma cells to anticancer drugs, resulting in reduced cell viability, migration, and invasion, which suggest a strategy to improve the response to chemotherapy and reduce tumorigenesis in human osteosarcoma. The American Society for Pharmacology and Experimental Therapeutics